Most localized prostate cancers (PCa) are indolent and will never become aggressive during a patient's lifetime. Many of these patients could benefit from active surveillance (AS), but uncertainty about their individual risk prompts them to choose radical prostatectomy (RP) or radiation therapy, which can negatively impact quality of life, with only ~10% of patients in the US electing AS. Among the key barriers that prevent a more widespread adoption of AS is the fact that the current 12-core systematic random prostate needle diagnostic biopsy (SR-Bx) protocol can miss areas of more advanced disease already present in the prostate in ~30% of patients, thus introducing under-staging and under-grading error at the time of diagnosis. This error seems to be higher among African-American (AA) men, who are at a disproportionally higher risk of developing aggressive PCa and of dying of their disease. Specifically, among AA men, existing predictors to determine AS eligibility seem to perform more poorly, the rate of high-grade tumors missed during biopsy is higher, and rates tumor progression while on AS are higher. Therefore, there is an urgent need to test more reliable biopsy approaches to better discriminate men with clinically insignificant disease (CiPCa), who will truly benefit from AS, from those with clinically significant PCa (CSPCa) who require definitive treatment. We have shown that among white men the use of MRI for identifying suspicious lesions and for targeting prostate biopsies to them with MRI-US image-fusion biopsy technique (MRUS-Bx) outperforms SR-Bx in CSPCa detection, cancer core length, cancer rate per core, cancer volume estimation, and detection of anterior cancers (more common among AA men). We now propose to undertake a randomized controlled trial to compare the detection rate of CSPCa between SR-Bx and MRUS-Bx among AA and white men, to provide better clinical tools to discriminate between CSPCa and CiSPCa and thus, in the long term, improve overall survival among AA men. AIM 1: We propose to enroll 400 men (200 AA, 200 white) with elevated PSA (>2.5 ng/mL) and negative digital rectal exam across 5 academic institutions and 1 private practice. Men will be randomized into two arms: 1) SR-Bx (12 cores) with an MRI 3-months after biopsy for men without CSPCa; 2) pre-biopsy MRI with MRUS- Bx (2 cores/lesion) for men MRI visible lesions (PIRADS > 3). We will compare biopsy detection rate of CSPCa and CiSPCa. AIM 2: we will validate among men who elect RP (~110 in the RCT) the accuracy of MRUS-Bx based on the agreement with findings from step-sectioned RP specimens. AIM 3: we will identify among men invited to participate and those enrolled in the RCT, determinants of a) study participation and b) treatment decision (AS vs radiation vs RP), and c) compare morbidity associated with either SR-Bx vs MRUS-Bx. The results of our study may change the standard of care and improve accuracy in the diagnosis of PCa among asymptomatic men, which will increase confidence in making the correct treatment decision (definitive treatment versus active surveillance), particularly AA men with PCa who are at the greatest disadvantage. 1